Transcriptomes of B cells in the context of adenoviral TGF-β1- or bleomycin-induced lung fibrosis in mice. Transcriptomes of B cells in the context of adenoviral TGF-β1- or bleomycin-induced lung fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is an irreversible diffuse parenchymal lung disease of poorly defined etiology. Patients with IPF frequently demonstrate distinctive lymphoplasmacellular infiltrations within remodeled lung tissue, the relevance of which in lung fibrogenesis is still understudied. Histopathological examination of explant lung tissue of patients with IPF revealed accentuated lymphoplasmacellular accumulates in close vicinity to or even infiltrating remodeled lung tissue. Similarly, we found significant accumulations of B cells interfused with T cells within remodeled lung tissue in two murine models of adenoviral TGF-β1 or bleomycin (BLM)-induced lung fibrosis. Such B cell accumulates coincided with significantly increased lung collagen deposition, lung histopathology and worsened lung function in WT mice. Importantly however, B cell deficient µMT KO mice responded similarly with lung tissue remodeling and worsened lung function upon either AdTGF-β1 or BLM treatment as did WT mice. Comparative transcriptomic profiling of sorted B cells collected from lungs of AdTGF-β1 and BLM exposed WT mice identified a large set of commonly regulated genes, however with significant enrichment observed for gene ontology terms (GO terms) apparently not related to lung fibrogenesis. Collectively, although we observed B cell accumulates in lungs of IPF patients as well as two experimental models of lung fibrosis, comparative profiling of characteristic features of lung fibrosis between WT and B cell-deficient mice did not support a major involvement of B cells in lung fibrogenesis in mice. Overall design: RNA samples of mice exposed to AdTGF-β1/AdCL or Bleomycin/saline for 14 or 21 days.

特发性肺纤维化（Idiopathic pulmonary fibrosis, IPF）是一种病因未明的不可逆性弥漫性肺实质疾病。IPF患者常于重塑肺组织内出现特征性淋巴浆细胞浸润，其在肺纤维化发生中的相关作用仍有待深入探究。对IPF患者切除肺组织的组织病理学检查显示，重塑肺组织邻近区域甚至浸润其中的淋巴浆细胞聚集现象显著增强。类似地，我们在两种腺病毒转化生长因子β1（adenoviral TGF-β1）或博来霉素（bleomycin, BLM）诱导肺纤维化的小鼠模型中，同样观察到重塑肺组织内存在大量与T细胞混杂的B细胞聚集。在野生型（wild type, WT）小鼠中，此类B细胞聚集与肺胶原沉积显著增加、肺组织病理学改变加重及肺功能恶化同步出现。但值得注意的是，B细胞缺陷的µMT敲除（µMT KO）小鼠在接受AdTGF-β1或BLM处理后，其肺组织重塑及肺功能恶化程度与野生型小鼠并无显著差异。对经AdTGF-β1和BLM处理的野生型小鼠肺组织分选得到的B细胞进行比较转录组分析，鉴定出大量共同调控的基因，然而这些基因显著富集的基因本体（Gene Ontology, GO）术语似乎与肺纤维化发生无关。综上，尽管我们在IPF患者及两种肺纤维化实验模型的肺组织中均观察到B细胞聚集，但对野生型与B细胞缺陷小鼠肺纤维化特征的比较分析并未支持B细胞在小鼠肺纤维化发生中发挥主要作用。实验整体设计：对经AdTGF-β1/AdCL或博来霉素/生理盐水处理14天或21天的小鼠采集RNA样本。